Women's health

..................................................

Cervical cancer
Search date October 2009
Pierre L Martin-Hirsch and Nicholas J Wood

ABSTRACT
INTRODUCTION: Worldwide, cervical cancer is the third most common cancer in women. In the UK, incidence fell after the introduction of
the cervical screening programme, to the current level of approximately 2334 women in 2008, with a mortality to incidence ratio of 0.33.
Survival ranges from almost 100% 5-year disease-free survival for treated stage Ia disease to 5–15% in stage IV disease. Survival is also
influenced by tumour bulk, age, and comorbid conditions. METHODS AND OUTCOMES: We conducted a systematic review and aimed to
answer the following clinical questions: What are the effects of interventions to prevent cervical cancer? What are the effects of interventions
to manage early-stage cervical cancer? What are the effects of interventions to manage bulky early-stage cervical cancer? We searched:
Medline, Embase, The Cochrane Library, and other important databases up to October 2009 (Clinical Evidence reviews are updated period-
ically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such
as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS:
We found 14 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the
quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and
safety of the following interventions: human papillomavirus (HPV) vaccine for preventing cervical cancer; conisation of the cervix for microin-
vasive carcinoma (stage Ia1), conisation of the cervix plus lymphadenectomy (stage Ia2 and low-volume, good prognostic factor stage Ib),
radical trachelectomy for low-volume stage Ib disease, neoadjuvant chemotherapy, radiotherapy, chemoradiotherapy, or different types of
hysterectomy versus each other for treating early-stage and bulky early-stage cervical cancer.

QUESTIONS
What are the effects of interventions to prevent cervical cancer?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
What are the effects of interventions to manage early-stage cervical cancer?. . . . . . . . . . . . . . . . . . . . . . . . . . 5
What are the effects of additional interventions to manage bulky early-stage cervical cancer?. . . . . . . . . . . . . 8

INTERVENTIONS
PREVENTION OF CERVICAL CANCER ADDITIONAL INTERVENTIONS IN BULKY EARLY-
STAGE CERVICAL CANCER
Unknown effectiveness
HPV vaccine (versus no vaccination) . . . . . . . . . . . . 3 Beneficial
Chemoradiotherapy (increased survival compared with
MANAGEMENT OF EARLY-STAGE CERVICAL radiotherapy) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
CANCER
Likely to be beneficial Unknown effectiveness

Conisation of the cervix for microinvasive carcinoma Neoadjuvant chemotherapy . . . . . . . . . . . . . . . . . . . 9

(stage Ia1)* (consensus that as effective as simple hys-
terectomy for this stage and preserves fertility) . . . . 5 To be covered in future updates
Radiotherapy versus surgery (consensus that both are Effects of interventions to manage locally advanced
likely to be beneficial but unclear how they compare)* disease
.......................................... 7 Effects of interventions to manage widespread
(metastatic) disease
Unknown effectiveness Effects of interventions to manage localised recurrent
Conisation plus lymphadenectomy versus hysterectomy disease
for stage Ia2 and low-volume stage Ib New . . . . . . 6 Effects of interventions to manage cervical cancer in
Radical trachelectomy plus lymphadenectomy (can pregnancy
preserve fertility compared with radical hysterectomy)
.......................................... 6 Footnote
Simple hysterectomy plus lymphadenectomy versus *Based on consensus
radical hysterectomy plus lymphadenectomy New . .
7

Key points

• Worldwide, cervical cancer is the third most common cancer in women.

In the UK, incidence fell after the introduction of the cervical screening programme to the current level of approx-
imately 2334 women in 2008, with a mortality to incidence ratio of 0.33.
About 80% of tumours are squamous type, and staging is based on the FIGO classification.
Survival ranges from almost 100% 5-year disease-free survival for treated stage Ia disease to 5–15% in stage
IV disease. Survival is also influenced by tumour bulk, age, and comorbid conditions.
Development of cervical cancer is strongly associated with HPV infection, acquired mainly by sexual intercourse.
© BMJ Publishing Group Ltd 2011. All rights reserved. ..................... 1 ..................... Clinical Evidence 2011;07:818
 Women's health
Cervical cancer
The peak prevalence of HPV infection is 20–40% in women aged 20 to 30 years, but in 80% of cases the infection
resolves within 12 to 18 months.
Other risk factors for cervical cancer include early onset of sexual activity, multiple sexual partners, long-term
use of oral contraceptives, tobacco smoking, low socioeconomic status, and immunosuppressive therapy.
• Vaccination against HPV is effective in preventing certain types of oncogenic HPV infection, and at reducing rates
of cervical intraepithelial neoplasia, but there has been insufficient long-term follow-up to assess effects on cervical
cancer rates.
• Conisation with adequate excision margins is considered effective for microinvasive carcinoma (stage Ia1), and
can preserve fertility, unlike simple hysterectomy; however, it has been associated with an increased risk of preterm
delivery and low birth weight.
Conisation is often performed for stage Ia1 disease, but evidence for its benefit is from observational studies
only.
• We don’t know how conisation of the cervix with pelvic lymphadenectomy and simple or radical hysterectomy
compare with each other for stage Ia2 and low volume stage 1b cervical cancer, as we found no RCTs.
• We don’t know how simple hysterectomy plus lymphadenectomy and radical hysterectomy plus lymphadenectomy
compare with each other, in early cervical cancer, as we found no RCT evidence.
• Limited observational evidence shows that radical trachelectomy plus lymphadenectomy results in similar disease-
free survival as radical hysterectomy in women with early-stage cervical cancer; however, we found no RCTs.
Radical trachelectomy plus lymphadenectomy can preserve fertility.
• Limited RCT evidence shows that radiotherapy is as effective as surgery in early-stage disease.
Overall and disease-free survival are similar after radiotherapy or radical hysterectomy plus lymphadenectomy,
but radiotherapy is less likely to cause severe adverse effects.
• Chemoradiotherapy improves survival compared with radiotherapy in women with bulky early-stage cervical cancer.
Combined chemoradiotherapy improves overall and progression-free survival when used either before or after
hysterectomy, but is associated with more haematological and gastrointestinal toxicity compared with radiother-
apy alone.
• The benefits of neoadjuvant chemotherapy plus surgery compared with radiotherapy alone are unknown.

DEFINITION Cervical cancer is a malignant neoplasm arising from the uterine cervix. About 80% of cervical
cancers are of the squamous type; the remainder are adenocarcinomas, adenosquamous carcino-
[1]
mas, and other rare types. Staging of cervical cancer is based on clinical evaluation (FIGO
[2]
classification; see table 1, p 13 ). Management is determined by tumour bulk and stage. Popu-
lation: This review deals with treatments for early-stage cancer (defined as FIGO stage Ia1, Ia2,
Ib1, and small IIa tumours) and bulky early-stage disease (defined as FIGO stage Ib2 and larger
IIa tumours).

INCIDENCE/ Cervical cancer is the third most common cancer in women, with about 529,000 new cases diag-
PREVALENCE nosed worldwide in 2008. Most (85%) cases occur in resource-poor countries that have no effective
[3]
screening programmes. The incidence of cervical cancer in the UK and Europe has greatly re-
duced since the introduction of a screening programme for detecting precancerous cervical intraep-
ithelial neoplasia. Cervical cancer incidence fell by 42% between 1988 and 1997 in England and
[4]
Wales. This fall has been reported to be related to the cervical screening programme. In England,
cervical cancer had an annual incidence of 2334 women in 2008, with a mortality to incidence ratio
[5]
of 0.33.

AETIOLOGY/ Risk factors for cervical cancer include sexual intercourse at an early age, multiple sexual partners,
RISK FACTORS tobacco smoking, long-term oral contraceptive use, low socioeconomic status, immunosuppressive
therapy, and micronutrient deficiency. Persistent infection by oncogenic, high-risk strains of HPV
[6] [7]
is strongly associated with the development of cervical cancer. HPV strains 16 and 18 cause
[7]
about 70% of cervical cancer and high-grade cervical intraepithelial neoplasia. The virus is ac-
quired mainly by sexual intercourse, and has a peak prevalence of 20% to 40% in women aged
20 to 30 years, although in 80% of cases the infection is transient and resolves within 12 to 18
[8] [9]
months. Women with persistent oncogenic HPV are at risk of developing high-grade pre-
cancer and ultimately cervical cancer.

PROGNOSIS Overall, 5-year disease-free survival is 50% to 70% for stages Ib2 and IIb, 30% to 50% for stage
[1]
III, and 5% to 15% for stage IV. In women who receive treatment, 5-year survival in stage Ia
approaches 100%, falling to 70% to 85% for stage Ib1 and smaller IIa tumours. Survival in women
with more locally advanced tumours is influenced by tumour bulk, the person's age, and coexistent
medical conditions. Mortality in untreated locally advanced disease is high.

© BMJ Publishing Group Ltd 2011. All rights reserved. ........................................................... 2

 Women's health
Cervical cancer
AIMS OF To reduce morbidity and mortality; to improve quality of life with minimal adverse effects.
INTERVENTION
OUTCOMES For question on prevention of cervical cancer: vaccine immunogenicity: seroconversion rates,
rates of HPV, rates of cervical intraepithelial neoplasia, rates of cervical cancer. For questions
on management of early-stage cervical cancer and bulky early-stage cervical cancer: mortality:
overall survival, progression-free survival; recurrence: local recurrence, distant recurrence;
quality of life; and adverse effects of treatment. Some treatments — including "fertility-preserving
treatments" — may affect fertility. We therefore examined the effects of treatment on pregnancy
rates and live-birth rate. Adverse effects of chemotherapy are usually graded according to severity,
using scales such as the Chassagne morbidity scale (grades 0–3), National Cancer Institute
Common Toxicity scale (grades 0–4), and the Southwest Oncology Group scale (grades 0–5);
unless otherwise stated, grade 0 refers to no adverse effects, and higher scores indicate a greater
severity of adverse effects.

METHODS Clinical Evidence search and appraisal October 2009. The following databases were used to
identify studies for this systematic review: Medline 1966 to October 2009, Embase 1980 to October
2009, and The Cochrane Database of Systematic Reviews and Cochrane Central Register of
Controlled Clinical Trials 2009, Issue 4 (1966 to date of issue). An additional search was carried
out of the NHS Centre for Reviews and Dissemination (CRD) — for the Database of Abstracts of
Reviews of Effects (DARE) and Health Technology Assessment (HTA). We also searched for re-
tractions of studies included in the review. Abstracts of the studies retrieved from the initial search
were assessed by an information specialist. Selected studies were then sent to the contributor for
additional assessment, using predetermined criteria to identify relevant studies. Study design criteria
for inclusion in this review were: published systematic reviews of RCTs and RCTs in any language,
including open studies because comparisons between radiotherapy and chemotherapy would be
difficult to blind for, and containing >20 individuals of whom >80% were followed up. There was no
minimum length of follow-up required to include studies. For the early-stage disease question, we
included RCTs that included solely women with stage Ia1, Ia2, Ib1, and small IIa tumours. For the
bulky early-stage disease question, we included RCTs that included solely women with stage Ib2
and IIa tumours, as well as studies that included women with stage Ib2 and IIa tumours in addition
to women with less-extensive (lower-stage) tumours. We excluded studies that included women
with tumours of stage IIb and above, unless they performed prespecified subgroup analyses in
women with bulky early-stage disease (stage Ib2 or IIa tumours). We included systematic reviews
of RCTs and RCTs where harms of an included intervention were studied applying the same study
design criteria for inclusion as we did for benefits. In addition we use a regular surveillance protocol
to capture harms alerts from organisations such as the FDA and the MHRA, which are added to
the reviews as required. To aid readability of the numerical data in our reviews, we round many
percentages to the nearest whole number. Readers should be aware of this when relating percent-
ages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed
a GRADE evaluation of the quality of evidence for interventions included in this review (see table,
p 15 ). The categorisation of the quality of the evidence (into high, moderate, low, or very low) reflects
the quality of evidence available for our chosen outcomes in our defined populations of interest.
These categorisations are not necessarily a reflection of the overall methodological quality of any
individual study, because the Clinical Evidence population and outcome of choice may represent
only a small subset of the total outcomes reported, and population included, in any individual trial.
For further details of how we perform the GRADE evaluation and the scoring system we use, please
see our website (www.clinicalevidence.com).

QUESTION What are the effects of interventions to prevent cervical cancer?

OPTION HPV VACCINE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Rates of cervical intraepithelial neoplasia

Compared with placebo Bivalent vaccine (HPV types 16, 18) may be more effective than placebo at reducing rates
of low-grade pre-invasive disease (defined as cervical intraepithelial neoplasia [CIN] grade 1) and high-grade pre-
invasive disease (defined as CIN grade 2 or 3). Quadrivalent vaccine (HPV types 6, 11, 16, 18) and univalent HPV-
16 vaccine (analysed together as a group) may be more effective than placebo at reducing rates of high-grade pre-
invasive disease; however, we don't know whether they are more effective at reducing rates of low-grade abnormal-
ity. We don't know whether vaccination is more effective than placebo at reducing rates of adenocarcinoma in situ
at 36 to 48 months (low-quality evidence).

Vaccine immunogenicity
Compared with placebo Bivalent vaccine (HPV types 16, 18) and quadrivalent vaccine (HPV types 6, 11, 16, 18)
seem more effective than placebo at increasing vaccine efficacy (assessed by persistence of infections and serocon-
version to HPV) at 12 months or longer (moderate-quality evidence).
© BMJ Publishing Group Ltd 2011. All rights reserved. ........................................................... 3
 Women's health
Cervical cancer
Note
We found no direct information about the effects of vaccination against HPV in reducing rates of cervical cancer.

For GRADE evaluation of interventions for cervical cancer, see table, p 15 .

Benefits: Human papillomavirus (HPV) vaccine versus placebo:

We found one systematic review (search date 2007) assessing the efficacy of the univalent (HPV-
16 virus-like particle vaccine), bivalent (HPV-16/18 virus-like particle vaccine), and quadrivalent
[10]
(HPV-6/11/16/18 virus-like particle vaccine) vaccines. We found one additional RCT comparing
three different formulations of prophylactic quadrivalent (HPV types 6, 11, 16, 18) vaccine (admin-
[11]
istered at day 1, month 2, and month 6) versus placebo. This RCT was excluded by the review;
[10]
however, we have included this RCT separately, because it fulfilled Clinical Evidence inclusion
criteria.

Prevention of cytologically/histologically detected lesions: The review found that bivalent

vaccine (HPV types 16, 18) significantly reduced rates of low-grade (cervical intraepithelial neoplasia
[CIN] grade 1) and high-grade (CIN grades 2 or 3) pre-invasive disease compared with placebo at
14.8 to 44 months (low grade: 2 RCTs; 7/9879 [0.1%] with vaccine v 106/9878 [1.1%] with placebo;
OR 0.06, 95% CI 0.03 to 0.16; high grade: 2 RCTs; 2/9879 [0.02%] with vaccine v 26/9878 [0.26%]
with placebo; OR 0.09, 95% CI 0.03 to 0.34). The review analysed RCTs assessing quadrivalent
and univalent HPV vaccines together. It found that quadrivalent vaccine (HPV types 6, 11, 16, 18)
and univalent HPV-16 vaccine significantly reduced rates of high-grade pre-invasive disease
compared with placebo at 36 to 48 months (3 RCTs [2 RCTs using quadrivalent vaccines; 1 RCT
using univalent vaccine]; 173/10,003 [2%] with vaccine v 312/10,010 [3%] with placebo; OR 0.54,
95% CI 0.30 to 0.98); but it found no significant difference between vaccine and placebo in rates
of low-grade abnormality (2 RCTs [1 using quadrivalent vaccine, 1 using univalent vaccine]; 45/3916
[1%] with vaccine v 138/3930 [4%] with placebo; OR 0.13, 95% CI 0.01 to 2.0). However, the review
reported significant statistical heterogeneity and inconsistency in the analyses of quadrivalent and
univalent vaccines, which it commented may have been because of the small number of included
RCTs, and different duration of treatments and number of outcomes in included RCTs. The review
found no significant difference between groups in rates of adenocarcinoma in situ after 36 to 48
months (2 RCTs [both using quadrivalent vaccines]; 6/8810 [0.07%] with vaccine v 13/8812 [0.15%]
with control; OR 0.45, 95% CI 0.12 to 1.73). However, rates were low, and the analysis may have
[10]
lacked power to detect a difference between groups.
Vaccine immunogenicity: The review found that bivalent vaccine significantly increased vaccine
efficacy (assessed by persistence of infection with HPV-16 and HPV-18) compared with placebo
at 12 months (3 RCTs; 104/13,606 [0.8%] with vaccine v 188/13,617 [1.4%] with placebo; OR 0.26,
95% CI 0.07 to 0.99). However, it reported significant statistical heterogeneity and inconsistency
in this analysis, which it commented may have been because of the small number and different
sample sizes of included RCTs, and because the RCTs were conducted in different countries. The
review found that for quadrivalent/univalent vaccine, only one RCT reported on protection against
persistent disease. It found that vaccine significantly increased protection compared with placebo
(1 RCT using univalent vaccine: OR 0.16, 95% CI 0.10 to 0.26; absolute numbers not reported).
[10]

The additional RCT (552 women) found that quadrivalent vaccine significantly reduced rates of
persistent infection or disease with HPV types 6, 11, 16, or 18 compared with placebo over 30
months (incidence per 100 woman-years at risk: 0.8 with vaccine v 7.2 with placebo; P <0.0001;
modified intention-to-treat analysis [529 women who were naive to HPV before enrolment and who
[11]
received at least 1 vaccination]). A follow-up analysis of the RCT assessed seroconversion. It
found that at 2 months (after dose 1), vaccine-induced anti-HPV responses were approximately
12 to 26 times higher than those in women receiving placebo (HPV-16: mean 147 mMU/mL with
vaccine v 6.4 mMU/mL with placebo; HPV-18: mean 14 mMU/mL with vaccine v 4.5 mMU/mL with
placebo; significance not assessed). The RCT reported that the anti-HPV response initially de-
[12]
creased, then plateaued and remained stable over 3 years' follow-up.

Harms: Human papillomavirus (HPV) vaccine versus placebo:

The review found that injection-site events such as pain, swelling, and redness were significantly
increased with bivalent vaccine compared with placebo (2 RCTs; 5925/9879 [60%] with vaccine v
4334/9878 [44%] with placebo; OR 1.74, 95% CI 1.27 to 2.40). It found no significant difference
between vaccine and placebo in systemic adverse effects (arthralgia, fatigue, fever, etc.) or serious
adverse effects (systemic adverse effects: 2 RCTs; 7974/9879 [81%] with vaccine v 7306/9878
[74%] with placebo; OR 1.18, 95% CI 0.70 to 1.89; serious adverse effects: 2 RCTs; 390/9879
[3.9%] with vaccine v 372/9878 [3.8%] with placebo; OR 1.05, 95% 0.91 to 1.21). The review found
no significant difference in adverse effects between quadrivalent vaccine and placebo (OR 1.16,
[10]
95% CI 0.94 to 1.43; number of RCTs in analysis and absolute numbers not reported). The
additional RCT found that adverse effects at the injection site (particularly pain) were slightly more
common in women receiving vaccine than placebo, but the RCT did not assess the significance
© BMJ Publishing Group Ltd 2011. All rights reserved. ........................................................... 4
 Women's health
Cervical cancer
[11]
of the difference between groups (250/272 [92%] with vaccine v 242/274 [88%] with placebo).
A modest increase (from 3% to 6%) in injection-site adverse effects was recorded with higher
doses of vaccine.

Comment: Clinical guide:

HPV infection does not necessarily result in cervical intraepithelial neoplasia (CIN). Most HPV in-
fection is transient; persistent HPV infection may result in CIN. A proportion of women will go on
to have high-grade CIN leading to cervical cancer. Complete seroconversion rate for type-specific
HPV infection, therefore, should translate to a reduction in type-specific CIN, but data about length
of immunity are lacking. Both vaccines (targeting HPV types 16 and 18 or targeting HPV types 16,
18, 6, and 11) have been evaluated in industry-funded trials alone, as of October 2009, when the
search for this review was completed. We found no RCTs that had sufficient sample size and length
of follow-up to assess the long-term effects of the vaccine in reducing rates of CIN and more impor-
tantly cervical cancer. Immunogenicity is not a clinically important measure, and long-term
surveillance of women included in these RCTs is important to make sure that the protection against
CIN is persistent.

QUESTION What are the effects of interventions to manage early-stage cervical cancer?

OPTION CONISATION OF THE CERVIX FOR MICROINVASIVE CARCINOMA (STAGE IA1). . . . . . . . . .

Note
We found no direct information from RCTs about conisation of the cervix compared with simple hysterectomy
for microinvasive carcinoma (stage Ia1). There is consensus that conisation of the cervix is effective for
microinvasive carcinoma (stage Ia1), provided that excision margins are clear of cancer or intraepithelial
neoplasia. Conisation of the cervix can, unlike hysterectomy, preserve fertility.

For GRADE evaluation of other interventions for cervical cancer, see table, p 15 .

Benefits: Conisation of the cervix versus simple hysterectomy:

We found no systematic review or RCTs comparing conisation of the cervix versus simple hysterec-
tomy for microinvasive carcinoma (stage Ia1).

Harms: Conisation of the cervix versus simple hysterectomy:

We found no RCTs.

Comment: Clinical guide:

There is consensus that conisation is effective for microinvasive carcinoma (stage Ia1), provided
that excision margins are clear of cancer or cervical intraepithelial neoplasia, and that there has
been an adequate review of histology by a pathologist and a multidisciplinary team experienced
in dealing with gynaecological cancer. Consensus is based on observational studies, and is con-
[13]
sistent with guidelines issued by the NHS cervical screening programme.

Conisation of the cervix can, unlike hysterectomy, preserve fertility. One systematic review (search
date 2004, 27 retrospective cohort studies) assessed outcomes after conservative treatments for
[14]
early invasive cervical lesions. It found that, compared with women who had not received
treatment, women who had received cold-knife conisation or large-loop excision of the transformation
zone (LLETZ) had significantly higher rates of preterm delivery and infants with low birth weight
(RR of preterm delivery v untreated controls: cold-knife conisation: RR 2.59, 95% CI 1.80 to 3.72;
LLETZ: RR 1.70, 95% CI 1.20 to 2.40; RR of low birth weight v untreated controls: cold-knife coni-
sation: RR 2.53, 95% CI 1.19 to 5.36; LLETZ: RR 1.82, 95% CI 1.09 to 3.06). Preterm delivery was
defined as delivery before 37 weeks and low birth weight as <2500 g. Analysis by depth of excised
tissue found that risks of preterm delivery increased further if the depth was >10 mm (RR of preterm
[14]
delivery v depth <10 mm: 2.6, 95% CI 1.3 to 5.3). An updated systematic review (search date
2007, 1 prospective cohort study, 20 retrospective studies) reported on severe pregnancy outcomes
in women with or without previous treatment for cervical intraepithelial neoplasia. It identified 12
of the same studies as the earlier review; however, it also identified 8 additional or subsequent
studies that were not identified by the earlier review. It found that knife cone biopsy was associated
with severe preterm delivery (<32/34 weeks) (5 studies; 18/343 [5%] with cold-knife conisation v
10,457/501,740 [2%] with untreated control; RR 2.78, 95% CI 1.72 to 4.51) and perinatal mortality
(7 studies: 33/761 [4%] with cold-knife conisation v 2305/442,385 [1%] with untreated control; RR
2.87, 95% CI 1.42 to 5.81). However, LLETZ was not significantly associated with such outcomes
(severe preterm delivery: 4 studies; 51/3392 [2.0%] with LLETZ v 9588/472,533 [1.4%] with untreated
control; RR 1.20, 95% CI 0.50 to 2.89; perinatal mortality: 7 studies: 22/3601 [0.6%] with LLETZ v
[15]
2296/442,377 [0.5%] with untreated control; RR 1.17, 95% CI 0.74 to 1.87).

© BMJ Publishing Group Ltd 2011. All rights reserved. ........................................................... 5

 Women's health
Cervical cancer
OPTION CONISATION OF THE CERVIX PLUS LYMPHADENECTOMY (STAGE IA2 AND LOW-VOLUME,
GOOD PROGNOSTIC FACTOR STAGE IB). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . New

Note
We found no direct information from RCTs about conisation of the cervix with pelvic lymphadenectomy
compared with simple or radical hysterectomy for microinvasive carcinoma stage Ia2 and low-volume stage
Ib carcinoma. Conisation of the cervix can, unlike hysterectomy, preserve fertility.

For GRADE evaluation of other interventions for cervical cancer, see table, p 15 .

Benefits: Conisation plus lymphadenectomy versus simple or radical hysterectomy for stage Ia2 and
low-volume stage Ib:
We found no systematic review or RCTs.

Harms: Conisation plus lymphadenectomy versus simple or radical hysterectomy for stage Ia2 and
low-volume stage Ib:
We found no RCTs.

Comment: Clinical guide:

Several reports have considered the potential role of limited treatment as opposed to radical hys-
terectomy and pelvic lymphadenectomy for low-volume, good prognostic factor cervical carcinoma.
[16] [17] [18] [19]
Four case series in women undergoing radical hysterectomy (1889 women) and
one case series in women with conservatively managed cervical cancer (17 women, 15 women
[20]
had fertility-sparing treatment, 12 women had vaginal or total abdominal hysterectomy) found
that the incidence of parametrial invasion in women with small-volume carcinoma, absent lymph-
vascular space involvement (LVSI), and negative lymph nodes was 0% to 0.6%. The clinical con-
sequences are that in women who have low-volume cervical cancers with good prognostic factors,
excisional biopsy with lymphadenectomy may be adequate treatment.

Conisation can preserve fertility. For further information on adverse pregnancy outcomes with
conisation see Clinical guide in conisation for stage Ia1 carcinoma, p 5 .

OPTION RADICAL TRACHELECTOMY PLUS LYMPHADENECTOMY. . . . . . . . . . . . . . . . . . . . . . . . . . .

Note
We found no direct information from RCTs about radical trachelectomy plus lymphadenectomy compared
with radical hysterectomy in women with early-stage cervical cancer. Unlike hysterectomy, radical trachelec-
tomy plus lymphadenectomy can preserve fertility.

For GRADE evaluation of other interventions for cervical cancer, see table, p 15 .

Benefits: Radical trachelectomy plus lymphadenectomy versus radical hysterectomy plus lymphadenec-
tomy:
We found no systematic review or RCTs.

Harms: Radical trachelectomy plus lymphadenectomy versus radical hysterectomy plus lymphadenec-
tomy:
We found no RCTs.

Comment: There are now several large case series, reviews, and descriptions of vaginal trachelectomy in the
[21] [22] [23]
published literature. Observational studies have demonstrated that in carefully selected
[21] [22]
women, pregnancy rates in women who want to conceive are between 50% and 70%.

In two large cohort studies, women who had undergone radical vaginal trachelectomy (VT) were
[24] [25]
compared with matched women who had undergone radical hysterectomy. The first study
(90 cases, 90 matched controls, retrospective comparison) found no significant difference between
groups in 5-year recurrence-free survival rates (95% with radical VT v 100% with radical hysterec-
tomy; P = 0.17). It also found no significant difference between groups in 5-year survival rates (99%
with radical VT v 100% with radical hysterectomy; P = 0.55; absolute results reported graphically;
[24]
total number of deaths in follow-up: 3 with radical VT v 1 with radical hysterectomy). The second
study (women with stage Ib disease, 40 cases who had trachelectomy, 110 matched controls who
had radical hysterectomy, retrospective design) found no significant difference in 5-year relapse-
[25]
free survival rate (96% with radical trachelectomy v 86% with radical hysterectomy; P >0.05).

Abdominal radical trachelectomy is a relatively new approach to fertility-sparing surgery compared

with the vaginal approach. Advocates of this approach recommend this technique for adenocarci-
nomas, when the disease might be higher in the cervical canal, and for large-volume disease or if
© BMJ Publishing Group Ltd 2011. All rights reserved. ........................................................... 6
 Women's health
Cervical cancer
there is any possibility that there might be deep stromal disease, in which case it is important to
[26]
ensure adequate resection of the parametrium. There are now several published case series
[27] [28]
on the abdominal approach. The only study to compare VT and abdominal trachelectomy
(AT) was a retrospective controlled study (43 women with stage Ib1 cervical cancer, 28 women
[26]
with attempted VT, 15 women with attempted AT). It found a significantly larger measurable
parametrium on AT compared with VT pathological specimens (median gross length of parametrium:
3.97 cm with AT v 1.45 cm with VT; P = 0.01) and significantly more women had at least one
parametrial lymph node detected on AT compared with VT specimens (women with parametrial
lymph nodes detected: 8/15 [53%] with AT v 0/28 [0%] with VT; P = 0.0002). This would suggest
that the abdominal approach removed more parametrium and surgically is more radical in its exci-
sions. In the limited number of cases analysed, the short-term and long-term morbidity and recur-
[26]
rence rates with AT seemed to be similar to rates with the vaginal approach. There is limited
information on pregnancy rates after AT from the early published case series (85 women with stage
Ia1 to Ib1 disease considered for AT, 38 had AT and attempted to conceive). The rate of successful
[27] [28]
pregnancy in women trying to conceive after AT from these studies was 14% to 56%.

OPTION SIMPLE HYSTERECTOMY PLUS LYMPHADENECTOMY (LOW-VOLUME STAGE IA2 AND

STAGE IB). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . New

Note
We found no direct information from RCTs about simple hysterectomy plus lymphadenectomy compared
with radical hysterectomy plus lymphadenectomy in women with early-stage cervical cancer.

For GRADE evaluation of other interventions for cervical cancer, see table, p 15 .

Benefits: Simple hysterectomy plus lymphadenectomy versus radical hysterectomy plus lymphadenec-
tomy:
We found no systematic review or RCTs.

Harms: Simple hysterectomy plus lymphadenectomy versus radical hysterectomy plus lymphadenec-
tomy:
We found no RCTs.

Comment: Clinical guide:

Several reports have considered the potential role of limited surgery as opposed to radical hysterec-
tomy for treatment of low-volume, good prognostic factor cervical carcinoma. Four case series in
[16] [17] [18] [19]
women undergoing radical hysterectomy (1889 women) and one case series in
women with conservatively managed cervical cancer (17 women, 15 women had fertility-sparing
[20]
treatment, 12 women had vaginal or total abdominal hysterectomy) found that the incidence
of parametrial invasion in women with small-volume carcinoma, absent lymphvascular space in-
volvement (LVSI), and negative lymph nodes was 0% to 0.6%. In women who have low-volume
cervical cancers with good prognostic factors, simple hysterectomy combined with lymphadenec-
tomy may be adequate surgery.

OPTION RADIOTHERAPY VERSUS SURGERY. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Mortality
Radiotherapy compared with radical hysterectomy plus lymphadenectomy Radiotherapy may be as effective as
surgery at increasing 5-year survival in women with stage Ib–IIa cervical cancer (low-quality evidence).

Recurrence
Radiotherapy compared with radical hysterectomy plus lymphadenectomy Radiotherapy may be as effective as
surgery (with or without adjuvant radiotherapy) at reducing recurrence and at increasing disease-free survival in
women with stage Ib–IIa cervical cancer (low-quality evidence).

Adverse effects
Radiotherapy compared with radical hysterectomy plus lymphadenectomy Surgery is associated with an increased
risk of adverse effects compared with radiotherapy in women with stage Ib–IIa cervical cancer (moderate-quality
evidence).

Note
There is consensus that both surgery and radiotherapy are likely to be beneficial.

For GRADE evaluation of interventions for cervical cancer, see table, p 15 .

© BMJ Publishing Group Ltd 2011. All rights reserved. ........................................................... 7

 Women's health
Cervical cancer
Benefits: Radiotherapy versus surgery:
We found no systematic review. We found one RCT (343 women stage Ib–IIa) comparing radio-
[29]
therapy versus radical hysterectomy plus lymphadenectomy (see comment below). It found no
significant difference between radiotherapy and surgery in 5-year or disease-free survival rates
(results presented graphically; AR for survival: about 83% for both groups; AR for disease-free
survival: about 74% for both groups; for both comparisons P value reported as not significant).
Recurrence rates were similar in both groups (42/170 [25%] with surgery v 44/167 [26%] with ra-
diotherapy; significance assessment not reported). However, the RCT did not report what proportion
[29]
of women with stage Ib cancer had stage Ib1 and stage Ib2 disease. The radical-hysterectomy
group in the RCT received a class III abdominal hysterectomy and pelvic lymphadenectomy;
women with enlarged para-aortic lymph nodes only received sampling and selective procedures.
[29]
Also, a large number of women in the surgery group (108/170 [64%]) received postoperative
pelvic radiotherapy. The decision to provide adjuvant radiotherapy was taken pre-operatively, based
on the presence of one or more known risk factors, such as UICC surgical stage greater than pT2a
(see table 2, p 14 ), <3 mm of uninvolved cervical stroma, cut-through, or lymph node metastases.
The trial excluded women considered medically unfit for surgery.

Harms: Radiotherapy versus surgery:

Surgery significantly increased the risk of severe adverse effects compared with radiotherapy
(grade 2–3 on the Chassagne morbidity scale; 28% with surgery v 12% with radiotherapy;
[29]
P <0.0004). Two women in the surgery group died (1 of spontaneous ileal perforation 11 months
after adjuvant radiotherapy and 1 of pulmonary embolism). Pelvic radiotherapy will usually result
in ablation of ovarian function. Certain surgical procedures can maintain fertility (see option on
conisation of the cervix, p 5 and option on radical trachelectomy plus lymphadenectomy, p 6 ).

Comment: Clinical guide:

Consensus regards both surgery and radiotherapy as likely to be beneficial.

QUESTION What are the effects of additional interventions to manage bulky early-stage cervical cancer?

OPTION CHEMORADIOTHERAPY VERSUS RADIOTHERAPY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Mortality
Chemoradiotherapy compared with radiotherapy Chemoradiotherapy used either before or after hysterectomy seems
more effective at increasing overall survival at 3 to 4 years in women with bulky early-stage cervical carcinoma
(moderate-quality evidence).

Progression-free survival
Chemoradiotherapy compared with radiotherapy Chemoradiotherapy used either before or after hysterectomy seems
more effective at increasing progression-free survival at 3 to 4 years in women with bulky early-stage cervical carci-
noma (moderate-quality evidence).

Note
Combined chemoradiotherapy has been associated with more haematological and gastrointestinal adverse effects
compared with radiotherapy.

For GRADE evaluation of interventions for cervical cancer, see table, p 15 .

Benefits: Chemoradiotherapy versus radiotherapy:

We found one systematic review (search date 2004), which identified two RCTs that compared
chemoradiotherapy versus radiotherapy alone in women with bulky early-stage cervical carcinoma.
[30]
The first RCT identified by the review (374 women with stage Ib2 tumours) compared
[31]
chemoradiotherapy versus radiotherapy, before hysterectomy, in all participants. It found that
chemoradiotherapy significantly increased progression-free survival and overall survival at 3 years
compared with radiotherapy (HR for progression 0.51, 95% CI 0.34 to 0.75; HR for mortality 0.54,
95% CI 0.34 to 0.86). The second RCT identified by the review included 268 women who had had
radical hysterectomy for stage Ia2, Ib, and IIa tumours (tumour diameter 0.2–5.2 cm; proportion of
[32]
women with stage Ia2 tumours not reported). The women had histologically confirmed positive
lymph nodes, positive parametrial involvement, or a positive surgical margin. The RCT found that
chemoradiotherapy significantly improved progression-free survival and overall survival at 4 years
compared with radiotherapy (estimated progression-free survival: AR 80% with chemoradiotherapy
v 63% with radiotherapy; adjusted HR 2.01, CI not reported; P = 0.003; estimated overall survival:
AR 81% with chemoradiotherapy v 71% with radiotherapy; adjusted HR 1.96, CI not reported;
P = 0.007).

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 Women's health
Cervical cancer
Harms: Chemoradiotherapy versus radiotherapy:
The first RCT in women with bulky early-stage cervical carcinoma found that, compared with radio-
therapy, chemoradiotherapy increased the proportion of women with moderate or severe adverse
effects (grade 3 or 4 toxicity according to National Cancer Institute Common Toxicity Criteria;
mainly haematological and gastrointestinal toxicity: 64/183 [35%] with chemoradiotherapy v 25/186
[31]
[13%] with radiotherapy; significance assessment not performed). The second RCT also found
that, compared with radiotherapy, chemoradiotherapy increased serious adverse effects (grade 4
Southwest Oncology Group criteria; mainly haematological toxicity: 27/122 [17%] with chemoradio-
[32]
therapy v 4/112 [4%] with radiotherapy; significance assessment not performed). We found
[33]
one systematic review (search date not reported), which assessed long-term toxicity. When
[31]
assessing the first RCT, the review suggested that the "same number of women" receiving
chemoradiotherapy and radiotherapy had toxicity (mainly bowel toxicity) at long-term follow-up
[33]
(11–61 months, median 36 months; absolute numbers not reported). The review found no data
[33]
on long-term toxicity from the second RCT.

Comment: One systematic review and individual patient meta-analysis has been published subsequent to the
[34]
search date of this Clinical Evidence review. This review pooled data for all women with bulky
cervical carcinoma (including later stages up to FIGO stage IV), and so only a subset of this popu-
lation may be relevant for this Clinical Evidence review. However, we will fully assess it for inclusion
at the next update.

OPTION NEOADJUVANT CHEMOTHERAPY. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Mortality
Compared with local treatment (radiotherapy, surgery, radiotherapy plus surgery) alone Neoadjuvant chemotherapy
(before surgery, radiotherapy, or both) may be more effective at increasing overall survival at 2 to 9 years in women
with bulky (stages Ib–IIa) tumours (low-quality evidence).

Progression-free survival
Compared with local treatment (radiotherapy, surgery, radiotherapy plus surgery) alone Cisplatin-based neoadjuvant
chemotherapy plus radical abdominal hysterectomy and pelvic lymphadenectomy may be more effective than radio-
therapy alone at increasing 5-year progression-free survival in women with bulky (stages Ib–IIa) tumours (very low-
quality evidence).

Recurrence
Compared with local treatment (radiotherapy, surgery, radiotherapy plus surgery) alone Neoadjuvant chemotherapy
(before surgery, radiotherapy, or both) may be more effective at reducing local recurrence and at increasing disease-
free survival at 5 years in women with bulky (stage Ib) tumours (low-quality evidence).

For GRADE evaluation of interventions for cervical cancer, see table, p 15 .

Benefits: Neoadjuvant chemotherapy (before local treatment using surgery, radiotherapy, or radio-
therapy plus surgery) versus local treatment alone:
[35] [36]
We found one systematic review (search date 2006), one additional RCT, and one subse-
[37]
quent RCT of neoadjuvant chemotherapy in women with cervical cancer.

The review identified 21 RCTs comparing neoadjuvant chemotherapy before surgery, radiotherapy,
or radiotherapy plus surgery, versus local treatment alone (radiotherapy, surgery, radiotherapy
[35]
plus surgery) in women with cervical cancer (including stages Ib–IVa). The review also identified
a further two RCTs for future inclusion, but did not include these in the analysis as the authors of
the review were awaiting individual patient data. We have included those RCTs from the review
that met Clinical Evidence inclusion criteria (RCTs which involved women with bulky early-stage
[35]
cervical cancer, and were published in full).

The first RCT identified by the review (205 women with stage Ib tumours, 57% with stage Ib2)
compared neoadjuvant chemotherapy versus no neoadjuvant chemotherapy before local treatment
[38]
for unresectable tumours. Local treatment involved surgery plus radiotherapy or radiotherapy
alone. Prespecified subgroup analysis found that neoadjuvant chemotherapy significantly improved
overall survival at 9 years, and reduced local recurrence in women with bulky (stage Ib2) tumours
(117 women, survival: 80% with neoadjuvant chemotherapy v 61% with no neoadjuvant
chemotherapy; P <0.01; local recurrence: 6% with neoadjuvant chemotherapy v 23% with no
[38]
neoadjuvant chemotherapy; P <0.01; absolute numbers not reported). The second RCT identified
by the review (124 women with stage Ib–IIa tumours) compared cisplatin-based neoadjuvant
chemotherapy (see comment below) plus radical abdominal hysterectomy and pelvic lymphadenec-
[39]
tomy versus radiotherapy alone. It found no significant difference between neoadjuvant
chemotherapy plus surgery and radiotherapy alone in overall survival at 2 years or in estimated 5-
year survival (2-year overall survival: 81% with neoadjuvant chemotherapy plus surgery v 84%
© BMJ Publishing Group Ltd 2011. All rights reserved. ........................................................... 9
 Women's health
Cervical cancer
with radiotherapy alone; 5-year overall survival: 70% with neoadjuvant chemotherapy plus surgery
v 62% with radiotherapy alone; P = 0.77 for both comparisons; absolute numbers not reported).
[39]
The third RCT identified by the review (441 women with stage Ib2–III tumours) compared cis-
platin-based neoadjuvant chemotherapy plus radical abdominal hysterectomy and pelvic lym-
[40]
phadenectomy versus radiotherapy alone. A subgroup analysis (87 women in each arm) of
stage Ib2 and IIa (>4 cm) tumours was prespecified at randomisation. It found that, compared with
radiotherapy alone, neoadjuvant chemotherapy plus surgery significantly increased 5-year overall
survival (69% with neoadjuvant chemotherapy plus surgery v 51% with radiotherapy alone; P = 0.01)
and 5-year progression-free survival (65% with neoadjuvant chemotherapy plus surgery v 51%
[40]
with radiotherapy alone; P = 0.01; absolute numbers not reported).

The additional RCT (identified by the review for future inclusion, 192 women with stage Ib–IIIb tu-
mours) compared neoadjuvant chemotherapy (cisplatin, vincristine, and bleomycin) before surgery
[36]
or radiotherapy versus surgery or radiotherapy alone. A post-hoc subgroup analysis in women
with stage Ib–IIa tumours found that neoadjuvant chemotherapy significantly increased disease-
free 5-year survival compared with no neoadjuvant chemotherapy, but found no significant difference
in overall 5-year survival between groups (126 women; disease-free 5-year survival: 77% with
neoadjuvant chemotherapy v 64% with no neoadjuvant chemotherapy; P <0.05; overall 5-year
survival: 79% with neoadjuvant chemotherapy v 73% with no neoadjuvant chemotherapy; reported
[36]
as not significant; P value not reported).

The subsequent RCT (106 women with stage Ib tumours, 64% with stage Ib2) compared cisplatin-
[37]
based neoadjuvant chemotherapy before surgery versus surgery alone. All women with deep
cervical invasion, parametrial extension, or positive lymph nodes also received postoperative radio-
therapy. A subgroup analysis in women with bulky (stage Ib2) tumours found that neoadjuvant
chemotherapy significantly improved overall 5-year survival compared with no neoadjuvant
chemotherapy (32/38 [84%] with neoadjuvant chemotherapy v 23/30 [77%] with no neoadjuvant
chemotherapy; P = 0.04). The RCT did not report recurrence rates separately for stage Ib1 and
Ib2 tumours. It found no significant difference in recurrence rates within 5 years between neoadjuvant
chemotherapy and no neoadjuvant chemotherapy; however, recurrence was lower with neoadjuvant
chemotherapy (10/52 [19%] with neoadjuvant chemotherapy v 19/54 [35%] with no neoadjuvant
[37]
chemotherapy; P = 0.08).

Harms: Neoadjuvant chemotherapy (before local treatment using surgery, radiotherapy, or radio-
therapy plus surgery) versus local treatment alone:
[35]
The systematic review gave no information on adverse effects.

The first RCT identified by the review reported that, in women receiving neoadjuvant chemotherapy,
there were 4 confirmed cases of peripheral neurotoxicity, one case of renal toxicity with transient
tubular failure, and two cases of mild pulmonary toxicity. It did not report on adverse effects in the
[38]
group that had no neoadjuvant chemotherapy.

The second RCT identified by the review found that rates of acute nausea and vomiting were
higher in women receiving neoadjuvant chemotherapy plus surgery than in women receiving radio-
therapy alone (59/68 [87%] with neoadjuvant chemotherapy plus surgery v 29/50 [58%] with radio-
[39]
therapy alone; significance assessment not performed for any of the comparisons). Rates of
intestinal obstruction were also higher (intestinal obstruction: 23/68 [34%] with neoadjuvant
chemotherapy plus surgery v 12/50 [24%] with radiotherapy alone; significance assessment not
performed for any of the comparisons). However, radiotherapy alone increased the proportion of
women with diarrhoea, and late radiation cystitis and late radiation proctitis compared with neoad-
juvant chemotherapy plus surgery (diarrhoea: 13/68 [19%] with neoadjuvant chemotherapy plus
surgery v 46/50 [92%] with radiotherapy alone; late radiation cystitis and late radiation proctitis:
22/68 [32%] with neoadjuvant chemotherapy plus surgery v 41/50 [82%] with radiotherapy alone;
significance assessment not performed for any of the comparisons). There were no treatment-re-
lated deaths. These results must be interpreted with caution, since several women in these groups
would have received adjuvant chemotherapy and adjuvant radiotherapy in addition to their primary
[39]
treatment, and this will influence toxicity.

The third RCT identified by the review gave no specific information on adverse effects, but no
[40]
treatment-related deaths occurred.
[36] [37]
The additional and subsequent RCTs also gave no information on adverse effects.

Comment: One systematic review (6 RCTs, 1072 women) has been published subsequent to the search date
of this Clinical Evidence review comparing neoadjuvant chemotherapy plus surgery versus surgery
[41]
alone. The review included RCTs in women with FIGO stages Ib–IIIb cervical cancer; however,
it presented subgroup analyses by stage (stage Ib only, and stages Ib–IIIb). We will assess it fully
© BMJ Publishing Group Ltd 2011. All rights reserved. .......................................................... 10
 Women's health
Cervical cancer
for inclusion at the next update of this Clinical Evidence review. The review suggested that there
might be potential benefits from neoadjuvant chemotherapy, but results were not significant. Further
trials are required to investigate the role of this treatment.

GLOSSARY
Adjuvant Chemotherapy or radiotherapy after definitive treatment (surgery).
Conisation of the cervix Involves removing the abnormal portion of the cervix using either a diathermy loop or a
scalpel.
Lymphadenectomy Surgical removal of lymph nodes.
Neoadjuvant chemotherapy Chemotherapy preceding local or definitive treatment (surgery or radiotherapy).
Radical hysterectomy Surgical removal of the cervix, uterus, vaginal cuff, pelvic lymph nodes, obturator lymph
nodes, paracervical tissue, and parametrial tissue.
Simple hysterectomy Surgical removal of the cervix and uterus only.
Chemoradiotherapy Involves both chemotherapy and radiotherapy given simultaneously for a short duration of time
(i.e., completing treatment within 5–6 weeks).
Low-quality evidence Further research is very likely to have an important impact on our confidence in the estimate
of effect and is likely to change the estimate.
Moderate-quality evidence Further research is likely to have an important impact on our confidence in the estimate
of effect and may change the estimate.
Very low-quality evidence Any estimate of effect is very uncertain.

SUBSTANTIVE CHANGES
Conisation plus lymphadenectomy for stage Ia2 and low-volume stage Ib New option added. Categorised as
Unknown effectiveness, as we found no RCT evidence to assess the effects of this comparison.
Simple hysterectomy plus lymphadenectomy versus radical hysterectomy plus lymphadenectomy New option
added. Categorised as Unknown effectiveness, as we found no RCT evidence to assess the effects of this compar-
ison.
[10]
HPV vaccine New evidence added. Categorisation unchanged (Unknown effectiveness), as there remains insuf-
ficient long-term data on the effects of the vaccine in reducing rates of cervical cancer.

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Pierre Leonard Martin-Hirsch

Department of Gynaecology
Royal Preston Hospital, Lancashire Teaching Hospitals NHS Foundation Trust
Preston
UK

Nicholas James Wood

Department of Gynaecology
Royal Preston Hospital, Lancashire Teaching Hospitals NHS Foundation Trust
Preston
UK

Competing interests: PLM-H declares that he has no competing interests. NJW has been reimbursed by Sanofi Pasteur, the manufacturer of Gardasil.
We would like to acknowledge the previous contributors of this review: Sudha Sundar, Amanda Horne, and Sean Kehoe.

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a
judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and
harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices.
Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research
we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the
categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately
it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest
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© BMJ Publishing Group Ltd 2011. All rights reserved. .......................................................... 12

 Women's health
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[2]
TABLE 1 FIGO staging of cervical cancer

Stage I The carcinoma is strictly confined to the cervix (extension to the corpus would be disregarded)
Stage Ia Invasive carcinoma that can be diagnosed only by microscopy, with deepest invasion 5 mm or less and largest extension not >7 mm
• Stage Ia1 Measured stromal invasion of 3.0 mm or less in depth and extension of 7.0 mm or less
• Stage Ia2 Measured stromal invasion of >3.0 mm and not >5.0 mm with an extension of not >7.0 mm
Stage Ib Clinically visible lesions limited to the cervix uteri or pre-clinical cancers greater than stage Ia*
• Stage Ib1 Clinically visible lesion 4.0 cm or less in greatest dimension
• Stage Ib2 Clinically visible lesion >4.0 cm in greatest dimension
Stage II Cervical carcinoma invades beyond the uterus, but not to the pelvic wall or to the lower third of the vagina
Stage IIa Without parametrial invasion
• Stage IIa1 Clinically visible lesion 4.0 cm or less in greatest dimension
• Stage IIa2 Clinically visible lesion >4 cm in greatest dimension
Stage IIb With obvious parametrial invasion
Stage III The tumour extends to the pelvic wall and/or involves lower third of the vagina and/or causes hydronephrosis or non-functioning kidney†
Stage IIIa Tumour involves lower third of the vagina, with no extension to the pelvic wall
Stage IIIb Extension to the pelvic wall and/or hydronephrosis or non-functioning kidney
Stage IV The carcinoma has extended beyond the true pelvis, or has involved (biopsy-proven) the mucosa of the bladder or rectum. A bullous oedema, as such, does not permit a case to be allotted to stage IV
Stage IVa Spread of the growth to adjacent organs
Stage IVb Spread to distant organs
* All macroscopically visible lesions — even with superficial invasion — are allotted to stage Ib carcinomas. Invasion is limited to a measured stromal invasion with a maximal depth of 5.00 mm and a horizontal
extension of not >7.00 mm. Depth of invasion should not be >5.00 mm taken from the base of the epithelium of the original tissue — superficial or glandular. The depth of invasion should always be reported in
millimetres, even in those cases with 'early (minimal) stromal invasion' (~1 mm). The involvement of vascular/lymphatic spaces should not change the stage allotment.
†On rectal examination, there is no cancer-free space between the tumour and the pelvic wall. All cases with hydronephrosis or non-functioning kidney are included, unless they are known to be due to another
cause.

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 Women's health
Cervical cancer
TABLE 2 UICC staging of cervical cancer

TNM definitions
The definitions of the primary tumour categories correspond to the FIGO stages
Primary tumour (T)
TX: Primary tumour cannot be assessed
T0: No evidence of primary tumour
Tis: Carcinoma in situ
T1/I: Cervical carcinoma confined to uterus (extension to corpus should be disregarded)
• T1a/IA: Invasive carcinoma diagnosed only by microscopy. All macroscopically visible lesions — even with superficial invasion — are T1b/IB. Stromal invasion with a maximal depth of 5 mm, measured from
the base of the epithelium, and a horizontal spread of 7 mm or less. Vascular space involvement, venous or lymphatic, does not affect classification
• T1a1/Ia1: Measured stromal invasion 3 mm or less in depth and 7 mm or less in horizontal spread
• T1a2/IA2: Measured stromal invasion >3 mm and not >5 mm, with a horizontal spread 7 mm or less
• T1b/IB: Clinically visible lesion confined to the cervix, or microscopic lesion greater than T1a2/IA2
• T1b1/IB1: Clinically visible lesion 4 cm or less in greatest dimension
• T1b2/IB2: Clinically visible lesion >4 cm in greatest dimension
T2/II: Cervical carcinoma invades beyond uterus but not to pelvic wall or to the lower third of the vagina
• T2a/IIa: Tumour without parametrial involvement
• T2b/IIb: Tumour with parametrial involvement
T3/III: Tumour extends to the pelvic wall and/or involves the lower third of the vagina, and/or causes hydronephrosis or non-functioning kidney
• T3a/IIIA: Tumour involves lower third of the vagina; no extension to pelvic wall
• T3b/IIIB: Tumour extends to pelvic wall and/or causes hydronephrosis or non-functioning kidney
T4/IVA: Tumour invades mucosa of the bladder or rectum, and/or extends beyond true pelvis (bullous oedema is not sufficient to classify a tumour as T4)
M1/IVB: Distant metastasis
Regional lymph nodes (N)
NX: Regional lymph nodes cannot be assessed
N0: No regional lymph node metastasis
N1: Regional lymph node metastasis
Distant metastasis (M)
MX: Distant metastasis cannot be assessed
M0: No distant metastasis
M1: Distant metastasis

© BMJ Publishing Group Ltd 2011. All rights reserved. ............................................................................................................ 14

 Women's health
Cervical cancer
TABLE GRADE evaluation of interventions for cervical cancer

Important out-
comes Vaccine immunogenicity, rates of cervical intraepithelial neoplasia, rates of cervical cancer, mortality, progression-free survival, recurrence, fertility, adverse effects
Number of studies Type of Consisten- Direct- Effect
(participants) Outcome Comparison evidence Quality cy ness size GRADE Comment
What are the effects of interventions to prevent cervical cancer?
[10]
5 (39,770) Rates of cervical in- HPV vaccine v placebo 4 0 –2 0 0 Low Consistency points deducted for statistical
traepithelial neopla- heterogeneity and different results for differ-
sia ent vaccines
[10]
4 (>27,223) Vaccine immuno- HPV vaccine v placebo 4 0 –1 0 0 Moderate Consistency point deducted for statistical
[12]
genicity heterogeneity
What are the effects of interventions to manage early-stage cervical cancer?
[29]
1 (343) Mortality Radiotherapy v radical hysterecto- 4 –1 0 –1 0 Low Quality point deducted for incomplete report-
my plus lymphadenectomy ing of results. Directness point deducted for
uncertainty about disease severity
[29]
1 (343) Recurrence Radiotherapy v radical hysterecto- 4 –1 0 –1 0 Low Quality point deducted for incomplete report-
my plus lymphadenectomy ing of results. Directness point deducted for
uncertainty about disease severity
[29]
1 (343) Adverse effects Radiotherapy v radical hysterecto- 4 0 0 –1 0 Moderate Directness point deducted for uncertainty
my plus lymphadenectomy about disease severity
What are the effects of additional interventions to manage bulky early-stage cervical cancer?
[31] [32]
2 (642) Mortality Chemoradiotherapy v radiotherapy 4 –1 0 0 0 Moderate Quality point deducted for incomplete report-
ing of results
[31] [32]
2 (642) Progression-free Chemoradiotherapy v radiotherapy 4 –1 0 0 0 Moderate Quality point deducted for incomplete report-
survival ing of results
[35] [38]
5 (609) Mortality Neoadjuvant chemotherapy (be- 4 0 –1 –1 0 Low Consistency point deducted for conflicting
[39] [40] [36] [37]
fore surgery, radiotherapy, or results. Directness point deducted for inclu-
both) v local treatment alone sion of smaller tumours in some RCTs
[40]
1 (174) Progression-free Neoadjuvant chemotherapy (be- 4 –2 0 –1 0 Very low Quality points deducted for sparse data and
survival fore surgery, radiotherapy, or incomplete reporting of results. Directness
both) v local treatment alone point deducted for inclusion of smaller tu-
mours in some RCTs
[38] [36]
3 (349) Recurrence Neoadjuvant chemotherapy (be- 4 0 –1 –1 0 Low Consistency point deducted for conflicting
[37]
fore surgery, radiotherapy, or results. Directness point deducted for inclu-
both) v local treatment alone sion of smaller tumours in some RCTs
Type of evidence: 4 = RCT. Consistency: similarity of results across studies. Directness: generalisability of population or outcomes. Effect size: based on relative risk or odds ratio.

© BMJ Publishing Group Ltd 2011. All rights reserved. ............................................................................................................ 15